New synthesis of tetrahydrobenzodifurans by iterative coupling of quinone monoacetals with alkene nucleophiles

Article abstract of DOI:10.3987/COM-15-S(T)41

A new efficient synthetic strategy of tetrahydrobenzodifurans has been developed by the repetitive [3+2] couplings of quinone monoacetals with alkene nucleophiles. Both the symmetrical and unsymmetrical tetrahydrobenzodifurans can be easily synthesized by this continuous method by altering the type of alkenes. These tetrahydrobenzodifurans have also become a useful precursor of highly-substituted benzofurans by dehydrogenation.

Full text of DOI:10.3987/COM-15-S(T)41

HETEROCYCLES, Vol. 93, No. 1, 2016
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HETEROCYCLES, Vol. 93, No. 1, 2016, pp. 295 - 309. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 31st August, 2015, Accepted, 1st October, 2015, Published online, 23rd October, 2015
DOI: 10.3987/COM-15-S(T)41
NEW SYNTHESIS OF TETRAHYDROBENZODIFURANS BY
ITERATIVE COUPLING OF QUINONE MONOACETALS WITH
ALKENE NUCLEOPHILES
Tohru Kamitanaka, Hitoho Takamuro, Kazuyuki Shimizu, Yudai Aramaki,
Toshifumi Dohi, and Yasuyuki Kita*,†
College of Pharmaceutical Science, Ritsumeikan University, 1-1-1 Nojihigasshi,
Kusatsu, Shiga, 525-8577, Japan. *Corresponding author. Tel. & fax:
+81-77-561-5829; e-mail: kita@ph.ritsumei.ac.jp (Y. Kita)
† Present Address: Research Organization of Science and Technology,
Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan.
Abstract – A new efficient synthetic strategy of tetrahydrobenzodifurans has been
developed by the repetitive [3+2] couplings of quinone monoacetals with alkene
nucleophiles. Both the symmetrical and unsymmetrical tetrahydrobenzodifurans
can be easily synthesized by this continuous method by altering the type of
alkenes. These tetrahydrobenzodifurans have also become a useful precursor of
highly-substituted benzofurans by dehydrogenation.
In Celebration of Professor Dr. Lutz F. Tietze on His 75th Birthday
INTRODUCTION
Dihydrobenzofuran skeletons exist in many natural products and biologically-active compounds, showing
a wide range of biological activities.1 In addition, dihydrobenzofurans can be converted into aromatized
benzofurans frequently found not only in biologically-active compounds,2 but also in artificial organic
materials,3 by the treatment with oxidants, such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).4
Moreover, the tetrahydrobenzodifuran skeletons, which have two dihydrofuran rings fused to one benzene
ring, are involved in several biologically-active compounds,5 and their oxidation products, benzodifurans,
are also utilized as biologically-active compounds6 and organic materials.7 Therefore, the development of

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a concise synthetic method of dihydrobenzofurans and tetrahydrobenzodifurans is an important objective
for contributing to the progress of pharmaceutical and material sciences.
Because of their attractiveness as a synthetic target, many organic chemists have reported the methods for
the synthesis of dihydrobenzofurans skeletons.1 Most of these reported methods featured the construction
of the furan ring skeletons, and the intramolecular O-alkyl or O-aryl bond formations were utilized as the
key step of the cyclizations. However, these methods usually involve the pre-functionalization of the
reaction site requiring many steps because the bond formations occurred in a step-by-step manner.
Although some two-component intermolecular coupling cyclization strategies were reported as the
short-step synthesis of these dihydrobenzofurans, the scope and application in natural products syntheses
are still limited.
Furthermore, tetrahydrobenzodifuran syntheses are rather rare and few examples are known (Scheme
1),5a,5c,8 despite their attractive characteristics. In 1982, Bladé-Font et al. reported the intermolecular
cyclization of the in situ generated quinone methide and methiodide (route a).8a An efficient cyclization
was achieved by the intramolecular nucleophilic substitution of an aryl alkyl ether promoted by butyl
lithium4a or a Grignard reagent5c (route b). The anodic oxidative [3+2] cyclization of a hydroquinone and
alkene nucleophile afforded the tetrahydrobenzodifuran in almost quantitative yield (route c).8b However,
these previous reports did not focus on the synthesis of the tetrahydrobenzodifurans, and only one
example of a tetrahydrobenzodifuran synthesis was mentioned in each report. Meanwhile, Lei et al.
recently reported the synthesis of tetrahydrobenzodifurans by the one-pot sequential [3+2] coupling
reactions of quinones and various styrene derivatives (route d).8c However, the unsymmetrical
tetrahydrobenzodifurans were difficult to obtain by this method, thus the synthetic products were limited
to symmetrical benzodifurans and very few examples of unsymmetrical benzodifurans. In addition, only
the two quinone compounds, 1,4-benzoquinone and 1,4-naphthoquinone, were applicable for the
reactions.
Scheme 1. General approaches to tetrahydrobenzodifurans

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As an improvement of the quinone strategy, we now assume that the synthesis of the
tetrahydrobenzodifurans 5 by the repetitive [3+2] coupling reactions of quinone monoacetals (QMAs) 1
and 4 via the deprotection of the methoxy group and oxidation of phenols is possible (Scheme 2). We
now report the new synthetic strategy of symmetrical and unsymmetrical tetrahydrobenzodifurans by the
iterative couplings of QMAs 1 and 4.
Scheme 2. New approach toward benzodifurans
RESULTS AND DISCUSSION
For the synthesis of the tetrahydrobenzodifurans 5, we focused on the utilization of the QMAs 1,
mono-protected quinones, as versatile precursors of the regio-controlled couplings to the allyl
acetalcarbonyl moieties. These QMAs 1 can be effectively obtained by treating phenols with hypervalent
iodine reagents, such as phenyl iodine(III) diacetate (PIDA), in methanol.9,10 Regarding the reactivity, all
the ring carbon atoms have an electrophilic nature due to the bifunctional structure, that is, the
,-unsaturated carbonyl and allyl acetal moieties. Although the 1,2- or 1,4-addition reactions to the
enone moiety have been reported,11,12 only a few examples of substitution reactions at the -position of
the carbonyl group were reported.13 On the other hand, we have recently realized substitution reactions by
the aid of a suitable acid promoter, and various -nucleophiles, such as aromatic nucleophiles,14 alkene
nucleophiles,15 and silyl enol ethers16 can be selectively introduced at the -position of the carbonyl
group of the QMAs 1. Accordingly, the [3+2] coupling of QMAs 1 and alkene nucleophiles 2,15 promoted
by a specific Brønsted acid, can afford dihydrobenzofurans 3 in high yields in the mixed solvent of
1,1,1,3,3,3-hexafluoroisopropanol (HFIP)17 and dichloromethane (Scheme 3).

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R3
R2
2
R2
R3
O
O
Brønsted acid
R1
R1
(CF3)2CHOH (HFIP)
CH2Cl2
rt
MeO OMe
OMe
quinone
monoacetals
(QMAs)
1
dihydrobenzofurans 3
Scheme 3. Previously reported [3+2] coupling reaction of quinone monoacetals
Our study regarding the tetrahydrobenzodifuran synthesis was thus started with the effective
demethylation of dihydrobenzofuran 3a, which has two types of ether bonds, that is, a methoxy group and
a reactive 2-phenyldihydrobenzofuran moiety (Scheme 4). By screening of the reductants, we found that
L-selectride, a bulky hydride source, effectively afforded the corresponding phenol from 3a,18 whereas
other deprotection methods did not give good results.19 The subsequent oxidation of the phenol ring was
smoothly proceeded by the standard QMA synthetic procedure using PIDA in methanol,20 and the desired
QMA 4a was obtained in a very high yield as a diastereo mixture (Scheme 4).
Ph
Ph
Ph
2a
O
O
O
MeO
1. L-Selectride
C6F5CO2H
THF, reflux, 36 h
HFIP/CH2Cl2
rt, 1 h
2. PhI(OAc)2 (PIDA)
MeOH, rt, 30 min.
MeO OMe
OMe
O
1a
3a: 93%
4a: 85% (for 2 steps)
Scheme 4. Synthesis of QMA 4a from QMA 1a
For the bicyclic QMA 4a, the [3+2] coupling reaction with styrene 2a and various alkene nucleophiles
2b-g under our previously reported conditions15a was then examined (Table 1). As a result, the
symmetrical dihydrobenzodifuran 5aa was successfully obtained as a mixture of two diastereomers21
(Entry 1). 4-Methyl- and 4-tert-butylstyrene (2b and 2c) were similarly transformed into the desired
products, 5ab and 5ac, in excellent yields, respectively (Entries 2 and 3). 4-Phenyl- and chlorostyrene (2d
and 2e) gave the products 5ad and 5ae in somewhat lower yields (Entries 4 and 5). The highly-substituted
product 5af was obtained in an excellent yield in which the (E)-alkene 2f selectively produced the vicinal
trans product (Entry 6).22 It is possible to construct the highly fused ring system of dihydronaphthalene

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2g in a good yield, and this product takes the cis-configuration due to its rigid bicyclic structure (Entry
7).23
Table 1. Scope of nucleophiles a
Ph
Ph
O
alkenes (2 equiv.)
O
MeO
C6F5CO2H (1 equiv.)
HFIP/CH2Cl2
rt, within 1 h
O
O
4a
R
5
entry
alkene
product
O
entry
alkene
product
Ph
6
O
Ph
O
MeO
O
(E)-2f
R
MeO
trans-5af: 96%
Ph
R
7
O
1
2
3
4
5
R = H (2a)
Me (2b)
t-Bu (2c)
Ph (2d)
R = H (5aa): 91%
Me (5ab): 99%
t-Bu (5ac): 99%
Ph (5ad): 69%
Cl (5ae): 67%
Cl (2e)
O
2g
5ag: 73%
a
The reactions were carried out using 2 equiv. of alkene nucleophiles 2 and 1 equiv. of
pentafluorobenzoic acid at room temperature.
Next, we briefly tested the scope of QMA substrates 4b-d having different ring substituent patterns
(Scheme 5) that were effectively synthesized by our established protocol (see Scheme 4). In QMAs 4b
and 4c the late-stage [3+2] coupling reactions selectively occurred at the vacant opposite side of the ring
substituents, and the unsymmetrical dihydrobenzodifurans 5bb and 5cb were thus obtained in high yields
(Eq. 1). Similarly, the highly-substituted unsymmetrical naphthalene 5db was obtained from the
naphthoquinone monoacetal 4d in a quantitative yield (Eq. 2).

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Ph
Ph
O
O
2b
R1
MeO
R1
C6F5CO2H
(1)
R2
HFIP/CH2Cl2
rt, within 2 h
R2
O
O
p-tolyl
R1 = Cl, R2 = H (4b)
R1 = H, R2 = Ph (4c)
R1 = Cl, R2 = H (5bb): 77%
R1 = H, R2 = Ph (5cb): 88%
Ph
O
Ph
O
2b
MeO
C6F5CO2H
(2)
HFIP/CH2Cl2
rt, within 1 h
O
O
p-tolyl
4d
5db: quant.
Scheme 5. Synthesis of unsymmetrical tetrahydrobenzodifurans by substituted QMAs 4b-d
Finally, we conducted the transformation of the dihydrobenzofurans 5ah into the aromatized benzofuran
6 for the synthetic elucidation of our developed strategy (Scheme 6). To obtain the
tetrahydrobenzodifuran 5ah, phenyl vinyl sulfide 2h was effectively coupled with QMA 4a under the
standard conditions, which showed the effective production of 5ah due to the mildness of the reaction
conditions. Next, the oxidation of sulfide tetrahydrobenzodifuran 5ah using mCPBA24 caused elimination
of the sulfide functionality, and the desired benzofuran 6 was obtained. Therefore, our new synthetic
route is useful for the construction of both tetrahydrobenzodifurans 4 and benzofurans, such as the mixed
benzofuran 6.
Ph
Ph
Ph
PhS
2h
O
O
O
mCPBA
MeO
C6F5CO2H
(see Ref. 15c)
HFIP/CH2Cl2
0 °C, 15 min.
CH2Cl2
rt, 1 h
O
O
O
PhS
5ah: 63%
6: 76%
4a
Scheme 6. Oxidative conversion of tetrahydrobenzodifuran into benzofuran 6

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CONCLUSION
In this study, we have newly developed an efficient synthetic strategy of tetrahydrobenzodifurans by the
iterative [3+2] coupling reactions of QMAs with styrene nucleophiles. The symmetrical and
unsymmetrical heterocyclic products could be synthesized with perfect regioselectivities by employing
QMAs instead of quinone compounds. The synthesized tetrahydrobenzodifuran can be effectively
converted into unique mixed benzofuran. Further investigations of the expeditious coupling strategy, such
as the asymmetric reaction and expansion of the substrate scope, are ongoing in our research group.
EXPERIMENTAL
Melting point (mp) is uncorrected. All 1H- and 13C-NMR spectra of the obtained products were measured
o
in CDCl3 by NMR spectrometers operating at 400 MHz (100 MHz for 13C-NMR) at 25 C. Chemical
shifts of 1H-NMR were recorded in parts per million (ppm, ) relative to tetramethylsilane ( = 0.00 ppm)
as an internal standard. Data are reported as follows: chemical shift in ppm (), multiplicity (s = singlet, d
= doublet, t = triplet, m = multiplet), coupling constant (J) in Hz, and integration. Chemical shifts of
13C-NMR were reported in ppm with the solvent as reference peak (CDCl3:  = 77.0 ppm). High
resolution mass measurements were performed by the Elemental Analysis Section of Osaka University.
Flash column chromatography was performed with Merck Silica-gel 60 (230-400 mesh) eluting with
hexane and ethyl acetate for isolation of the products. Analytical thin-layer chromatography (TLC) was
carried out on Merck Silica-gel F254 plates (0.25 mm). The spots and bands were detected by UV light of
irradiation (254, 365 nm) and/or by staining with 5% phosphomolybdic acid followed by heating. Unless
otherwise noted, all experiments were carried out at room temperature in open flask without care of
moisture.
Materials
QMA 1a was prepared from 4-methoxyphenol by the conventional oxidation procedure using
phenyliodine(III) diacetate (PIDA) in methanol.8 Other QMAs 1 were also prepared according to the
method. All other chemicals including the alkene nucleophiles 2, pentafluorobenzoic acid, and solvents
such as hexafluoroisopropanol (HFIP), for the reactions were obtained from commercial suppliers and
used as received without further purification.
Procedure for the synthesis of 7a-methoxy-2-phenyl-2,3-dihydrobenzofuran-5(7aH)-one (4a) from
QMA 1a (Scheme 4)

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To a solution of QMA 1a (1.54 g, 10 mmol) and syrene 2a (1.04 g, 20 mmol) in the mixture of HFIP (25
mL) and dichloromethane (25 mL), pentafluorobenzoic acid (2.12 g, 10 mmol) was added in one portion
at room temperature. The reaction mixture was stirred for 1 h and then solvent was removed in vacuo.
The residue was purified by column chromatography on silica-gel (hexane/EtOAc = 10/1) to give
2,3-dihydro-5-methoxy-2-phenylbenzofuran 3a (2.04 g, 9.0 mmol) in 90% yield.
Then, to a solution of 3a (2.04 g, 9 mmol) in THF (18 mL), L-selectride (1.0 M in THF, 27 mL, 27 mmol)
was added dropwise and the reaction mixture was refluxed for 36 h. After completion of the reaction, the
reaction mixture was cooled to room temperature, which was diluted with ether and was quenched with
water. The organic layer was washed with aqueous 1 M HCl and brine. The organic layer was dried over
anhydrous sodium sulfate, then filtered, concentrated, and purified by short column chromatography on
silica-gel (hexane/EtOAc = 5/1) to give a corresponding phenol 3’a (1.91 g, 9.0 mmol) in a quantitative
yield.
Finally, to a solution of 3’a (1.91 g, 9.0 mmol) in methanol (45 mL), PIDA (2.90 g) was added in one
portion at room temperature. The reaction mixture was stirred for 30 minutes and then quenched with
saturated aqueous NaHCO3 and extracted with EtOAc three times. Organic layer was washed with brine
and dried over anhydrous sodium sulfate, then filtered, concentrated, and purified by column
chromatography on silica-gel (hexane/EtOAc = 5/1) to give QMA 4a (1.85 g, 7.7 mmol) in 85% yield.
QMA 4a was obtained as the mixture of two diastereomers.
7a-Methoxy-2-phenyl-2,3-dihydrobenzofuran-5(7aH)-one (4a) (mixture of two diastereomers)
1
A yellow-colored solid; mp 65-67 °C; H-NMR (400 MHz, CDCl3): 2.62 (dd, J = 17.1, 3.9 Hz, 1H),
3.02-3.14 (m, 2H), 3.27 and 3.31 (s, 6H), 3.46-3.53 (m, 1H), 5.23-5.28 (m, 1H), 5.47 (dd, J = 9.2, 3.9 Hz,
1H), 6.09 (s, 1H), 6.13 (s, 1H), 6.28 (m, 2H), 6.97 (d, J = 10.2 Hz, 1H), 7.05 (d, J = 10.3 Hz, 1H),
13
7.21-7.49 (m, 10H) ppm; C-NMR (100 MHz, CDCl3): 37.0, 37.6, 50.5, 80.0, 82.5, 97.5, 98.3, 121.6,
122.2, 125.8, 126.7, 128.2, 128.3, 128.6, 128.7, 130.1, 130.8, 139.1, 139.8, 141.0, 141.1, 157.8, 158.3,
185.9 ppm; IR (KBr): 3054, 2929, 2828, 1684, 1655, 1287, 1133, 1088, 1033, 960, 765 cm-1; HRMS:
(MALDI-TOF) calcd for C15H15O3 [M+H]+; 243.1021, found 243.1016.
The physical and spectral data of the products 3a matched those previously reported.15
Typical procedure for the coupling of QMA 4a with alkene nucleophiles 2 leading to benzodifurans
5.
To a stirred solution of QMA 4a (242 mg, 1.0 mmol) and alkene nucleophile 2a (208 mg, 2.0 mmol) in
the mixture of HFIP (2.5 mL) and dichloromethane (2.5 mL), pentafluorobenzoic acid (212 mg, 1.0

HETEROCYCLES, Vol. 93, No. 1, 2016
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mmol) was added in one portion at room temperature. The reaction mixture was stirred for 1 h, then
solvent as removed in vacuo. The residue was purified by column chromatography on silica-gel
(hexane/EtOAc = 10/1) to give 2,6-diphenyl-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran 5aa (286 mg,
0.91 mmol) in 91% yield. The product 5aa was obtained as the mixture of two diastereomers.21
2,6-Diphenyl-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran (5aa)
1
A colorless solid; mp 153-156 °C; H-NMR (400 MHz, CDCl3): 3.14-3.20 (m, 2H), 3.56 (dd, J = 16.1,
9.3 Hz, 2H), 3.56 (t, J = 8.8 Hz, 2H), 6.68 (s, 2H), 7.27-7.41 (m, 10H) ppm; 13C-NMR (100 MHz,
CDCl3): 38.8, 38.9, 84.4, 105.8, 125.7, 125.8, 127.9, 128.6, 142.0, 153.9 ppm; IR (KBr): 3064, 3035,
2906, 2853, 1476, 1449, 1376, 1222, 1199, 1137, 968, 908, 857, 745, 697 cm-1; HRMS: (MALDI-TOF)
calcd for C22H18O2 [M]+; 314.1307, found 314.1301.
2-Phenyl-6-(p-tolyl)-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran (5ab)
A colorless solid; mp 135-137 °C; 1H-NMR (400 MHz, CDCl3): 2.33 (s, 3H), 3.16 (dd, J = 15.6, 8.8 Hz,
2H), 3.49-3.58 (m, 2H), 5.66-5.74 (m, 2H), 6.66 (s, 1H), 6.67 (s, 1H), 7.16 (d, J = 8.3 Hz, 2H), 7.28-7.40
(m, 7H) ppm; 13C-NMR (100 MHz, CDCl3): 21.1, 38.8 (x 4), 84.4(x 2), 105.8, 125.6, 125.8 (x 3), 127.9,
128.6, 129.2, 137.7, 139.0, 142.0, 153.8, 153.9 ppm; IR (KBr): 3035, 2914, 2851, 1477, 1450, 1223, 1199,
1137, 920, 855, 816, 749, 696 cm-1; HRMS: (MALDI-TOF) calcd for C23H20O2 [M]+; 328.1463, found
328.1458.
2-(4-(tert-Butyl)phenyl)-6-phenyl-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran (5ac)
A colorless solid; mp 98-102 °C; 1H-NMR (400 MHz, CDCl3): 1.30 (s, 9H), 3.13-3.22 (m, 2H) 3.50-3.58
(m, 2H), 5.67-5.74 (m, 2H), 6.66 (s, 1H), 6.68 (s, 1H), 7.27-7.40 (m, 9H) ppm; 13C-NMR (100 MHz,
CDCl3): 31.3, 34.5, 38.5 (x 2), 38.8 (x 2), 84.3 (x 2), 105.8, 125.4, 125.6 (x 2), 125.7, 125.8, 125.9, 127.9,
128.5, 138.8, 142.0, 150.9, 153.8, 153.9 ppm; IR (KBr): 3059, 3030, 2960, 2871, 1482, 1450, 1361, 1310,
1266, 1227, 1194, 1140, 972, 930, 837, 745, 698 cm-1; HRMS: (MALDI-TOF) calcd for C26H26O2 [M]+;
370.1933, found 370.1927.
2-([1,1’-Biphenyl]-4-yl)-6-phenyl-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran (5ad)
1
A colorless solid; mp 183-185 °C; H-NMR (400 MHz, CDCl3): 3.14-3.24 (m, 2H), 3.54-3.62 (m, 2H),
5.71-5.79 (m, 2H), 6.70 (s, 2H), 7.29-7.48 (m, 10H), 7.56-7.59 (m, 4H) ppm; 13C-NMR (100 MHz,
CDCl3): 38.8, 38.9, 84.2, 84.4, 105.8 (x 2), 125.7, 125.8, 126.3, 127.1, 127.3, 127.4, 128.0, 128.6, 128.8,
140.8, 140.9, 142.0, 153.9 ppm; IR (KBr): 3060, 3032, 2923, 2850, 1475, 1450, 1375, 1199, 1137, 912,
750 cm-1; HRMS: (MALDI-TOF) calcd for C28H22O2 [M]+; 390.1620, found 390.1614.

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2-(4-Chlorophenyl)-6-phenyl-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran (5ae)
A colorless solid; mp 140-144 °C; 1H-NMR (400 MHz, CDCl3): 3.10 (dd, J = 15.6, 7.8 Hz, 1H), 3.16 (dd,
J = 15.6, 8.3 Hz, 1H), 3.56 (dd, J = 14.6, 9.3 Hz, 2H), 5.67-5.74 (m, 2H), 6.67 (s, 2H), 7.28-7.40 (m, 9H)
13
ppm; C-NMR (100 MHz, CDCl3): 38.8 (x 3), 38.9, 83.6, 84.4, 105.8, 105.9 (x 3), 125.3, 125.4, 125.7,
125.9, 127.1, 128.0, 128.6, 128.7, 133.6, 140.6, 142.0, 153.7 (x 2), 154.0 ppm; IR (KBr): 3089, 3034,
2907, 1476, 1450, 1374, 1222, 1198, 1137, 1093, 969, 917, 857, 823, 751 cm-1; HRMS: (MALDI-TOF)
calcd for C22H17O2Cl [M]+; 348.0917, found 348.0912.
2-(4-Methoxyphenyl)-3-methyl-6-phenyl-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran (5af)
1
A colorless solid; mp 90-91 °C; H-NMR (400 MHz, CDCl3): 1.35 (dd, J = 6.8, 2.0 Hz, 3H), 3.13-3.20
(m, 1H), 3.34-3.41 (m, 1H), 3.56 (dd, J = 15.6, 9.3 Hz, 1H), 3.80 (s, 3H), 5.06 (d, J = 8.8 Hz, 1H), 5.72 (t,
13
J = 8.8 Hz, 1H), 6.23 (s, 1H), 6.66 (s, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.28-7.43 (m, 7H) ppm; C-NMR
(100 MHz, CDCl3): 17.6, 17.7, 38.8, 45.6 (x 2), 55.3, 84.4 (x 2), 92.7, 104.7 (x 2), 105.9, 106.0, 113.9,
125.6, 125.7 (x 2), 125.8, 127.6 (x 2), 127.9, 128.6 (x 2), 131.5, 132.7, 142.0, 153.4, 153.9, 159.6 ppm;
IR (KBr): 3035, 2956, 2929, 1513, 1443, 1249, 1149, 969, 828, 760, 701 cm-1; HRMS: (MALDI-TOF)
calcd for C24H22O3 [M]+; 358.1569, found 358.1564.
9-Phenyl-6,6a,9,10,12,12a-hexahydro-5H-naphtho[7,8-d]benzo[1,2-b:4,5-b’]difuran (5ag)
1
A colorless solid; mp 213-215 °C; H-NMR (400 MHz, CDCl3): 1.76-1.84 (m, 1H), 2.00-2.07 (m, 1H),
2.60-2.67 (m, 1H), 2.71-2.77 (m, 1H), 3.14 (dd, J = 15.6, 8.3 Hz, 1H), 3.53 (dd, J = 16.1, 9.8 Hz, 1H),
3.58-3.64 (m, 1H), 5.63 (d, J = 8.3 Hz, 1H), 5.71 (t, J = 8.8 Hz, 1H), 6.60 (s, 1H), 6.74 (s, 1H), 7.14 (d, J
= 6.8 Hz, 1H), 7.22-7.40 (m, 7H), 7.51 (d, J = 6.8 Hz, 1H) ppm; 13C-NMR (100 MHz, CDCl3): 27.6, 27.9,
38.8, 41.6, 82.1, 84.4, 105.3, 106.1, 125.8 (x 2), 126.6, 128.0, 128.2, 128.4, 128.6, 130.1, 130.8, 133.6,
138.8, 142.1, 153.6, 153.8 ppm; IR (KBr): 3060, 3032, 2922, 2882, 1477, 1448, 1120, 1142, 942, 917,
795, 757 cm-1; HRMS: (MALDI-TOF) calcd for C24H20O2 [M]+; 340.1463, found 340.1458.
4-Chloro-2-phenyl-7-(p-tolyl)-1,2,7,8-tetrahydrobenzo[1,2-b:4,3,-b’]difuran (5bb)
A colorless oily compound; 1H-NMR (400 MHz, CDCl3): 2.34 (s, 3H), 3.17-3.26 (m, 2H), 3.57-3.66 (m,
2H), 5.75 (t, J = 8.8 Hz, 1H), 5.81 (t, J = 8.8 Hz, 1H), 6.57 (s, 1H), 7.17 (d, J = 7.3 Hz, 2H), 7.27-7.41 (m,
7H) ppm; 13C-NMR (100 MHz, CDCl3): 14.1, 21.1, 22.6, 31.5, 37.96, 38.0, 39.5, 39.6, 84.5, 84.9, 104.19,
104.2, 111.4, 111.5, 124.60, 124.61, 125.7, 127.0, 128.1, 128.6, 129.27, 129.29, 137.9, 137.91, 138.4,
138.5, 141.4, 149.6, 154.13, 154.14 ppm; IR (KBr): 3029, 2919, 2855, 1597, 1516, 1495, 1450, 1356,

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305
1310, 1230, 1196, 1173, 973, 934,911, 816, 754, 699 cm-1; HRMS: (MALDI-TOF) calcd for C23H19O2Cl
[M]+; 362.1074, found 362.1068.
4,7-Diphenyl-2-(p-tolyl)-1,2,7,8-tetrahydrobenzo[1,2-b:4,3,-b’]difuran (5cb)
1
A colorless oily compound; H-NMR (400 MHz, CDCl3): 2.33 and 2.34 (s, 3H), 3.06-3.15 (m, 2H),
3.46-3.59 (m, 2H), 5.73-5.81 (m, 2H), 6.86 (s, 1H), 7.15-7.18 (m, 2H), 7.26-7.44 (m, 10H), 7.73-7.75 (m,
2H) ppm; 13C-NMR (100 MHz, CDCl3): 21.1, 37.6, 37.7, 84.0, 84.1, 84.20, 84.22, 106.95, 106.97, 121.6,
122.27, 122.28, 123.77, 123.78, 125.6, 125.67, 125.68, 126.9, 127.9, 128.2, 128.3, 128.59, 128.61, 129.2,
137.4, 137.6, 139.2, 139.3, 142.00, 142.03, 151.6, 154.9 ppm; IR (KBr): 3053, 3029, 2920, 2856, 1601,
1514, 1472, 1453, 1407, 1259, 1179, 971, 912, 855, 768, 695 cm-1; HRMS: (MALDI-TOF) calcd for
C29H24O2 [M]+; 404.1776, found 404.1771.
2-Phenyl-5-(p-tolyl)-2,3,4,5-tetrahydronaphtho[1,2-b:4,3,-b’]difuran (5db)
A colorless solid; mp 111-114 °C; 1H-NMR (400 MHz, CDCl3): 2.33 and 2.34 (s, 3H), 3.20-3.31 (m, 2H),
3.63-3.77 (m, 2H), 5.88-5.97 (m, 2H), 7.15-7.17 (m, 2H), 7.32-7.45 (m, 9H), 7.95-7.98 (m, 2H), ppm;
13C-NMR (100 MHz, CDCl3): 21.1, 38.6, 38.7, 84.3 (x 3), 115.9, 116.0, 119.4 (x 2), 121.8, 121.9, 125.0
(x 2), 125.7 (x 3), 125.8, 127.9, 128.6 (x 2), 129.2 (x 2), 137.7, 139.4, 142.5, 142.6, 149.3, 149.4 ppm; IR
(KBr): 3025, 2924, 2849, 1449, 1394, 1257, 1030, 881, 764 cm-1; HRMS: (MALDI-TOF) calcd for
C27H22O2 [M]+; 378.1620, found 378.1614.
2-Phenyl-6-(phenylthio)-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran (5ah)
1
A colorless oily compound; H-NMR (400 MHz, CDCl3): 3.10-3.18 (m, 2H), 3.52-3.65 (m, 2H),
5.68-5.74 (m, 1H), 6.16 (dd, J = 8.8, 4.4 Hz, 1H), 6.68-6.69 (m, 2H), 7.25-7.39 (m, 8H), 7.54 (d, J = 6.8
13
Hz, 2H) ppm; C-NMR (100 MHz, CDCl3): 37.2 (x 2), 38.7, 38.8, 84.4, 84.5, 89.6, 89.7, 105.6 (x 2),
106.9 (x 2), 125.2 (x 2), 125.7, 125.8, 126.0, 127.5, 128.0, 128.6, 128.9, 131.7 (x 2), 134.0 (x 2), 141.9,
141.9, 152.1, 154.3 ppm; IR (KBr): 3056, 3033, 2904, 2846, 1584, 1481, 1448, 1312, 1226, 1178, 1143,
913, 744, 695 cm-1; HRMS: (MALDI-TOF) calcd for C22H18O2S [M]+; 346.1028, found 346.1022.
Synthesis of benzofuran 6 from tetrahydrobenzodifuran 5ah (Scheme 6)
To the stirred solution of tetrahydrobenzofuran 5ah (104 mg, 0.3 mmol) in dichloromethane (3 mL),
m-chloro perbenzoic acid (70%, 74 mg, 0.3 mmol) was added. After consumption of the starting material,
it was quenched with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, then filtered, and concentrated in vacuo. The resulting residue
was purified by column chromatography on silica-gel (hexane/EtOAc = 25/1) to give benzofuran 6.

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2-Phenyl-2,3-dihydrobenzo[1,2-b:4,5-b’]difuran (6)
1
A colorless oily compound; H-NMR (400 MHz, CDCl3): 3.29 (dd, J = 15.6, 8.8 Hz, 1H), 3.69 (dd, J =
15.6, 9.3 Hz, 1H), 5.79 (t, J = 8.8 Hz, 1H), 6.67 (dd, J = 2.4, 1.0 Hz, 1H), 6.99 (s, 1H), 7.28-7.43 (m, 6H),
7.54 (d, J = 2.4 Hz, 1H) ppm; 13C-NMR (100 MHz, CDCl3): 38.6, 84.6, 99.9, 106.8, 107.7, 124.5, 125.7,
127.1, 128.0, 128.6, 141.9, 145.3, 150.5, 155.9 ppm; IR (KBr): 3035, 2920, 2854, 1593, 1527, 1450, 1381,
1189, 1160, 1120, 1030, 984, 865, 750 cm-1; HRMS: (MALDI-TOF) calcd for C16H12O2 [M]+; 236.0837,
found 236.0832.
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research (A) from the JSPS and a Grant-in-Aid
for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts”
from MEXT. T.D. also acknowledges support from Grant-in-Aid for Young Scientists (A) and
Challenging Exploratory Research as well as research fund from the Asahi Glass Foundation. T.K. thanks
Grant-in-Aid for JSPS Fellows.
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caused decomposition of the dihydrobenzofurans structure. Thiolate was not effective for such an
electron-rich arene, and upon heating ring-opening product without deprotection of the methoxy
group was produced.
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diastereomers and by measuring 1H-NMR of the product mixture.
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See Ref. 15c.
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1H-NMR spectrum. These coupling-constant values well match with those of related trans and cis
cyclic compounds reported in our previous literatures. See Ref. 15.
24. We reported the efficient oxidative conversion of dihydrobenzofurans having O,S-acetal to
benzofurans by employing several reaction conditions. See Ref. 15c.